Medicinal Chemistry of Fetal Hemoglobin Inducers for Treatment of β-Thalassemia

Roberto      Gambari; Eitan      Fibach

Abstract

In this review we summarize the achievements of medicinal chemistry in the field of pharmacological approaches to the therapy of β-thalassemia using molecules able to stimulate the production of fetal hemoglobin (HbF). We first describe the molecular basis of the pathology and the biochemical rational of using HbF inducers for therapy; we then outlined the in vitro and in vivo experimental systems suitable for screening of such potential drugs, and finally we describe the different classes of compounds with emphasis on their advantages and disadvantages in the treatment. The results of these reviewed studies indicate that: (a) HbF inducers can be grouped in several classes based on their chemical structure and mechanism of action; (b) clinical trials with some of these inducers demonstrate that they are effective in ameliorating the symptoms of β-thalassemia; (c) a good correlation was found between HbF stimulation in vivo and in vitro indicating that in vitro testing might be predictive of the in vivo response; (d) combined use of different inducers might maximize the effect, both in vitro and in vivo. However, (e) the response to HbF inducers, evaluated in vitro and in vivo, is variable, and some patients might be refractory to HbF induction by certain inducers; in addition, (f) several considerations call for caution, including the fact that most of the inducers exhibit in vitro cytotoxicity, predicting side effects in vivo following prolonged treatments.

Keywords: Fetal hemoglobin, β-thalassemia, Histone deacethylases, Hydroxyurea, DNA-binding drugs, Rapamycin

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